Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant familial cancer syndrome characterized by the frequent occurrence of tumors in the parathyroids, gastro-intestinal endocrine tissues (e.g., gastrinomas, tumors of the endocrine duodenum), enteropancreatic endocrine tissues, the anterior pituitary, and occasionally other sites. In keeping with the hypothesis originally articulated by Knudson for retinoblastoma (see Knudson (1971) Proc. Natl. Acad. Sci. U.S.A. 68:820), most of the genes responsible for familial cancer syndromes are of the tumor suppressor type. In such a circumstance, affected individuals have inherited one altered copy of the responsible gene from an affected parent (they are heterozygotes), but the tumors have lost the remaining functional copy (the “wild-type allele”) as a somatic event (becoming non-functional homozygotes). Germ-line homozygocity would be fatal. Thus the inheritance pattern of the syndrome is dominant, but the mechanism of tumorigenesis is recessive.
Finding the gene responsible for such a cancer syndrome would provide a new window into the mechanism of tumorigenesis, would facilitate accurate early diagnosis, and would, through screening, identify individuals predisposed to cancer. In the case of MEN1, a patient in an affected kindred manifesting any one of the classic features of the syndrome is at risk for the development of the other associated tumors. According to standard medical practice, periodic screening of both affected individuals and unaffected relatives is considered essential. Standard practice recommends that this be done at least biannually and include, e.g., review of the history for symptoms suggestive of peptic ulcer disease, diarrhea, nephrolithiasis, hypoglycemia, and hypopituitarism; physical examination for features of acromegaly and subcutaneous lipomas; and measurement of serum Ca, phosphate (PO4), gastrin, and prolactin. Further laboratory testing, CT or MRI of the sella turcica, and other diagnostic maneuvers should also be performed when clinically indicated. Prior to this invention, no protein or gene-based diagnostic test was available.
The significance of discovering such a tumor suppressor gene extends beyond affected pedigrees, as the same tumor suppressor gene is often found to play a role (by somatic mutation of both alleles in individuals born homozygous for a wild-type, functional allele) in sporadic cases of various neoplasms. These non-hereditary tumors are typically endocrine tumors. Identification of non-hereditary mutations can give information about the origin of the tumor and its prognosis. Furthermore, treatments arising from the gene's discovery will lead to the amelioration and/or prevention of such tumors.
Thus, there exists a great need to identify the gene associated with MEN1 and FMEN1, as characterization such a gene which would allow identification of those individuals with MEN1, provide lifesaving diagnostic tests, therapeutic treatment regimens, and prognostic evaluations of individuals with FMEN1 and individuals with somatic mutations involving both alleles resulting in non-hereditary tumors. The present invention fulfills these and other needs.